ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Ferroptosis, a recently identified non-apoptotic form of cell death reliant on iron, is distinguished by an escalation in lipid reactive oxygen species (ROS) that are iron-dependent. This phenomenon has a strong correlation with irregularities in iron metabolism and lipid peroxidation. Salvia miltiorrhiza Bunge (DS), a medicinal herb frequently utilized in China, is highly esteemed for its therapeutic effectiveness in enhancing blood circulation and ameliorating blood stasis, particularly during the treatment of cardiovascular diseases (CVDs). Numerous pharmacological studies have identified that DS manifests antioxidative stress effects as well as inhibits lipid peroxidation. However, ambiguity persists regarding the potential of DS to impede ferroptosis in cardiomyocytes and subsequently improve myocardial damage post-myocardial infarction (MI). AIM OF THE STUDY: The present work focused on investigating whether DS could be used to prevent the ferroptosis of cardiomyocytes and improve post-MI myocardial damage. MATERIALS AND METHODS: In vivo experiments: Through ligation of the left anterior descending coronary artery, we constructed both a wild-type (WT) and NF-E2 p45-related factor 2 knockout (Nrf2-/-) mouse model of MI. Effects of DS and ferrostatin-1 (Fer-1) on post-MI cardiomyocyte ferroptosis were examined through detecting ferroptosis and myocardial damage-related indicators as well as Nrf2 signaling-associated protein levels. In vitro experiments: Erastin was used for stimulating H9C2 cardiomyocytes to construct an in vitro ferroptosis cardiomyocyte model. Effects of DS and Fer-1 on cardiomyocyte ferroptosis were determined based on ferroptosis-related indicators and Nrf2 signaling-associated protein levels. Additionally, inhibitor and activator of Nrf2 were used for confirming the impact of Nrf2 signaling on DS's effect on cardiomyocyte ferroptosis. RESULTS: In vivo: In comparison to the model group, DS suppressed ferroptosis in cardiomyocytes post-MI and ameliorated myocardial damage by inducing Nrf2 signaling-related proteins (Nrf2, xCT, GPX4), diminishing tissue ferrous iron and malondialdehyde (MDA) content. Additionally, it enhanced glutathione (GSH) levels and total superoxide dismutase (SOD) activity, effects that are aligned with those of Fer-1. Moreover, the effect of DS on alleviating cardiomyocyte ferroptosis after MI could be partly inhibited through Nrf2 knockdown. In vitro: Compared with the erastin group, DS inhibited cardiomyocyte ferroptosis by promoting the expression of Nrf2 signaling-related proteins, reducing ferrous iron, ROS, and MDA levels, but increasing GSH content and SOD activity, consistent with the effect of Fer-1. Additionally, Nrf2 inhibition increased erastin-mediated ferroptosis of cardiomyocytes through decreasing Nrf2 signaling-related protein expressions. Co-treatment with DS and Nrf2 activator failed to further enhance the anti-ferroptosis effect of DS. CONCLUSION: MI is accompanied by cardiomyocyte ferroptosis, whose underlying mechanism is probably associated with Nrf2 signaling inhibition. DS possibly suppresses ferroptosis of cardiomyocytes and improves myocardial damage after MI through activating Nrf2 signaling.
Subject(s)
Ferroptosis , Myocardial Infarction , Myocytes, Cardiac , Salvia miltiorrhiza , Signal Transduction , Animals , Male , Mice , Rats , Cell Line , Disease Models, Animal , Ferroptosis/drug effects , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Salvia miltiorrhiza/chemistry , Signal Transduction/drug effectsABSTRACT
Abdominal malignant tumors originated from cancers, such as vater ampulla carcinoma (VAC) and pancreatic cancer (PC), often invades the portal vein (PV) and the superior mesenteric vein (SMV) upon metastasis. Surgical removal of these tumors leads to sacrifice of parts of these vessels that need to be reconstructed with autograft tissues. Current options for the replacement tissue all have their limitations in certain aspects. Therefore, improved interstitial material for the reconstruction with better tissue compatibility is urgently needed. In the present study, we explored the potential of hepatic round ligament (HRL) as a candidate tissue for the task from the biomechanical point of view. We reveal that HRL and PV share similar geometrical parameters in terms of vascular cavity diameter and wall thickness. In addition, they also have similar elastic properties and tissue flexibility and intensity upon increased cavity pressure. Our study strongly supports HRL as potential replacement tissue for PV reconstruction in term of mechanical properties and encourages further biological studies to be performed on these two tissues for further verification.
